The invention relates to cancer treatment, specifically to an improved stable anticancer agent which is a derivative of apoptolidin.
A microbial product, apoptolidin, has been isolated from Nocardiopsis sp. which selectively sensitizes cancer cells to apoptosis. (Kim, J. W., et al., Antibiot. (1997) 50:628-630; Hayakawa, Y., et al., J. Am. Chem. Soc. (1998) 120:3524-3525.) While apoptolidin shows considerable potency in its ability to induce apoptosis selectively, it is unstable under alkaline conditions, and, unfortunately, under neutral, physiological conditions. The present invention provides a more stable derivative of apoptolidin which retains the selective apoptosis inducing activity of apoptolidin.
The invention is directed to a stabilized derivative of apoptolidin which lacks the oleandrose and olivomycose sugars. The derivative is stable under physiological conditions and a potent selective antitumor agent.
Thus, in one aspect, the invention is directed to a compound of the formula 
and the pharmaceutically acceptable esters and/or ethers thereof.
In other aspects, the invention is directed to pharmaceutical or veterinary compositions of the compounds of formula 1 and to methods to treat tumors by administering the compound of formula 1 or a pharmaceutical composition thereof. xe2x80x9cTreatmentxe2x80x9d includes both therapeutic and prophylactic effects. In still other aspects, the invention is directed to a method to synthesize the compound of formula 1 by conversion from apoptolidin and optional esterification and on conversion to either forms.